Effectiveness of novel iron regulators in the treatment of diabetic nephropathy
DOI:
https://doi.org/10.15584/ejcem.2023.3.28Keywords:
acute kidney injury, chronic kidney disease, end-stage renal disease, iron chelators, renal iron handlingAbstract
Introduction and aim. The novel advancements of upcoming iron regulators used to treat diabetic nephropathy have implicated a common manifestation of combination chelation therapy used to eliminate end-stage renal disease associated with inflammation and iron imbalance that is altered by renal iron absorption. However, iron accumulation in the clustered kidneys that filter blood may cause problems that affect diabetic blood sugar regulation.
Material and methods. A well-designed method was employed to discover relevant research publications on iron chelators and their potential to treat diabetic nephropathy. “Iron chelators”, “diabetic nephropathy”, “end-stage renal disease”, and “chelation therapy” were searched in Google Scholar, Web of Science, PubMed, and EMBASE.
Analysis of literature. Although the specific etiology and development have not been fully explored, emerging evidence on iron pathophysiology helps comprehend the pathogenesis of acute kidney damage and chronic kidney disease, which crucially provides novel iron chelation therapy techniques. Ferroptosis and hepcidin marker proteins increase oxidative/nitrifying stress and kidney injury. Iron chelator medicines including deferoxamine, deferasirox, and deferiprone were tested as prophylactic strategies.
Conclusion. This article covers both preclinical and clinical aspects of iron chelators to avoid diabetic nephropathy, including novel iron therapies that must be reviewed when selecting dosing regimens.
Downloads
References
van Raaij S, van Swelm R, Bouman K, et al. Tubular iron deposition and iron handling proteins in human healthy kidney and chronic kidney disease. Sci Rep. 2018;8(1):9353. doi: 10.1038/s41598-018-27107-8
Magee C, Grieve DJ, Watson CJ, Brazil DP. Diabetic Nephropathy: a Tangled Web to Unweave. Cardiovasc Drugs Ther. 2017;31(5-6):579-592. doi: 10.1007/s10557-017-6755-9
Oltean S, Coward R, Collino M, Baelde H. Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Avenues. Biomed Res Int. 2017;2017:1-1. doi: 10.1155/2017/3146524
Murphy F, Bennett L, Jenkins K. Managing anaemia of chronic kidney disease. British Journal of Nursing. 2010;19(20):1281-1286. doi: 10.12968/bjon.2010.19.20.79681
Besarab A, Coyne DW. Iron supplementation to treat anemia in patients with chronic kidney disease. Nat Rev Nephrol. 2010;6(12):699-710. doi: 10.1038/nrneph.2010.139
Chaudhary K, Chilakala A, Ananth S, et al. Renal iron accelerates the progression of diabetic nephropathy in the HFE gene knockout mouse model of iron overload. American Journal of Physiology-Renal Physiology. 2019;317(2):512-517. doi: 10.1152/ajprenal.00184.2019
Ganz T, Nemeth E. Iron Balance and the Role of Hepcidin in Chronic Kidney Disease. Semin Nephrol. 2016;36(2):87-93. doi: 10.1016/j.semnephrol.2016.02.001
Ganz T. Systemic Iron Homeostasis. Physiol Rev. 2013;93(4):1721-1741. doi: 10.1152/physrev.00008.2013
Abbaspour N HRKR. Review on iron and its importance for human health. J Res Med Sci. 2014;19(2):164-174.
Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1(3):191-200. doi: 10.1016/j.cmet.2005.01.003
Coyne DW. Hepcidin: clinical utility as a diagnostic tool and therapeutic target. Kidney Int. 2011;80(3):240-244. doi: 10.1038/ki.2011.141
Walker VJ, Agarwal A. Targeting Iron Homeostasis in Acute Kidney Injury. Semin Nephrol. 2016;36(1):62-70. doi: 10.1016/j.semnephrol.2016.01.003
Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Investig. 2004;114(1):5-14. doi: 10.1172/JCI22353
Jacobs A. Serum ferritin and iron stores. Fed Proc. 1977;36(7):2024-2027.
Sharma S, Leaf DE. Iron Chelation as a Potential Therapeutic Strategy for AKI Prevention. J Am Soc Nephrol. 2019;30(11):2060-2071. doi: 10.1681/ASN.2019060595
Pavkov ME, Knowler WC, Bennett PH, Looker HC, Krakoff J, Nelson RG. Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians. Kidney Int. 2006;70(10):1840-1846. doi: 10.1038/sj.ki.5001882
Hoste EAJ, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411-1423. doi: 10.1007/s00134-015-3934-7
Selim M. Deferoxamine Mesylate. Stroke. 2009;40(3),1:90-91. doi: 10.1161/STROKEAHA.108.533125
Kianian F, Seifi B, Kadkhodaee M, Sadeghipour HR, Ranjbaran M. Nephroprotection through Modifying the Apoptotic TNF-α/ERK1/2/Bax Signaling Pathway and Oxidative Stress by Long-term Sodium Hydrosulfide Administration in Ovalbumin-induced Chronic Asthma. Immunol Invest. 2022;51(3):602-618. doi: 10.1080/08820139.2020.1858860
Molina-Jijón E, Zarco-Márquez G, Medina-Campos ON, et al. Deferoxamine pretreatment prevents Cr(VI)-induced nephrotoxicity and oxidant stress: Role of Cr(VI) chelation. Toxicology. 2012;291(1-3):93-101. doi: 10.1016/j.tox.2011.11.003
Gafter-Gvili A, Schechter A, Rozen-Zvi B. Iron Deficiency Anemia in Chronic Kidney Disease. Acta Haematol. 2019;142(1):44-50. doi: 10.1159/000496492
National Collaborating Centre for Chronic Conditions (UK). Anaemia Management in Chronic Kidney Disease: National Clinical Guideline for Management in Adults and Children. London: Royal College of Physicians (UK); 2006. PMID: 20945579. Published online June 2015.
Agarwal AK. Iron metabolism and management: focus on chronic kidney disease. Kidney Int Suppl. 2021;11(1):46-58. doi: 10.1016/j.kisu.2020.12.003
Sheetz M, Barrington P, Callies S, et al. Targeting the hepcidin–ferroportin pathway in anaemia of chronic kidney disease. Br J Clin Pharmacol. 2019;85(5):935-948. doi: 10.1111/bcp.13877
Brosius FC, He JC. JAK inhibition and progressive kidney disease. Curr Opin Nephrol Hypertens. 2015;24(1):88-95. doi: 10.1097/MNH.0000000000000079
Babitt JL, Lin HY. Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD. Am J Kidney Dis. 2010;55(4):726-741. doi: 10.1053/j.ajkd.2009.12.030
Hu J, Fan X, Meng X, Wang Y, Liang Q, Luo G. Evidence for the Involvement of JAK/STAT/SOCS Pathway in the Mechanism of Tangshen Formula-Treated Diabetic Nephropathy. Planta Med. 2014;80(08/09):614-621. doi: 10.1055/s-0034-1368454
Berthier CC, Zhang H, Schin M, et al. Enhanced Expression of Janus Kinase–Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy. Diabetes. 2009;58(2):469-477. doi: 10.2337/db08-1328
Zhu M, Wang H, Chen J, Zhu H. Sinomenine improve diabetic nephropathy by inhibiting fibrosis and regulating the JAK2/STAT3/SOCS1 pathway in streptozotocin-induced diabetic rats. Life Sci. 2021;265:118855. doi: 10.1016/j.lfs.2020.118855
Berthier CC, Zhang H, Schin M, et al. Enhanced Expression of Janus Kinase–Signal Transducer and Activator of Transcription Pathway Members in Human Diabetic Nephropathy. Diabetes. 2009;58(2):469-477. doi: 10.2337/db08-1328
Nemeth E, Ganz T. Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int J Mol Sci. 2021;22(12):6493. doi: 10.3390/ijms22126493
Sun M, Bu W, Li Y, et al. Danzhi Jiangtang Capsule ameliorates kidney injury via inhibition of the JAK-STAT signaling pathway and increased antioxidant capacity in STZ-induced diabetic nephropathy rats. Biosci Trends. 2018;12(6):595-604. doi:10.5582/bst.2018.01255
Saboor M, Zehra A, Hamali H, Mobarki A. Revisiting Iron Metabolism, Iron Homeostasis and Iron Deficiency Anemia. Clin Lab. 2021;67:10.7754/Clin.Lab.2020.200742. doi: 10.7754/Clin.Lab.2020.200742
Yu SMW, Bonventre J V. Acute Kidney Injury and Progression of Diabetic Kidney Disease. Adv Chronic Kidney Dis. 2018;25(2):166-180. doi: 10.1053/j.ackd.2017.12.005
Allison SJ. Mechanism of AKI sensitivity in diabetic nephropathy. Nat Rev Nephrol. 2014;10(9):484-484. doi: 10.1038/nrneph.2014.125
Lei Q, Xu F, Liang S, et al. Clinical Acute Kidney Injury and Histologic Acute Tubular-Interstitial Injury and Their Prognosis in Diabetic Nephropathy. Nephron. 2022;146(4):351-359. doi: 10.1159/000520944
Mishra J. Amelioration of Ischemic Acute Renal Injury by Neutrophil Gelatinase-Associated Lipocalin. J Am Soc Nephrol. 2004;15(12):3073-3082. doi: 10.1097/01.ASN.0000145013.44578.45
Mo M, Gao Y, Deng L, Liang Y, Xia N, Pan L. Association Between Iron Metabolism and Acute Kidney Injury in Critically Ill Patients With Diabetes. Front Endocrinol (Lausanne). 2022;13. doi: 10.3389/fendo.2022.892811
Rouault TA. Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease. Dis Model Mech. 2012;5(2):155-164. doi: 10.1242/dmm.009019
Ismail THB, Ali BH, Bashir AA. Influence of iron, deferoxamine and ascorbic acid on gentamicin-induced nephrotoxicity in rats. Gen Pharmacol. 1994;25(6):1249-1252. doi: 10.1016/0306-3623(94)90145-7
Cui HJ, He H yu, Yang AL, et al. Efficacy of Deferoxamine in Animal Models of Intracerebral Hemorrhage: A Systematic Review and Stratified Meta-Analysis. PLoS One. 2015;10(5):e0127256. doi: 10.1371/journal.pone.0127256
Choi CW, Lee J, Lee HJ, Park HS, Chun YS, Kim B Il. Deferoxamine Improves Alveolar and Pulmonary Vascular Development by Upregulating Hypoxia-inducible Factor-1α in a Rat Model of Bronchopulmonary Dysplasia. J Korean Med Sci. 2015;30(9):1295. doi: 10.3346/jkms.2015.30.9.1295
Ghaith MM, El-Boshy M, Almasmoum H, et al. Deferasirox and vitamin D3 co-therapy mitigates iron-induced renal injury by enhanced modulation of cellular anti-inflammatory, anti-oxidative stress, and iron regulatory pathways in rat. J Trace Elem Med Biol. 2022;74:127085. doi: 10.1016/j.jtemb.2022.127085
Zou C, Liu X, Liu R, et al. Effect of the oral iron chelator deferiprone in diabetic nephropathy rats. J Diabetes. 2017;9(4):332-340. doi: 10.1111/1753-0407.12420
Zou C, Xie R, Bao Y, et al. Iron chelator alleviates tubulointerstitial fibrosis in diabetic nephropathy rats by inhibiting the expression of tenascin C and other correlation factors. Endocrine. 2013;44(3):666-674. doi: 10.1007/s12020-013-9907-0
Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci. 2013;124(3):139-152. doi: 10.1042/CS20120198
Meza Letelier CE, San Martín Ojeda CA, Ruiz Provoste JJ, Frugone Zaror CJ. Pathophysiology of diabetic nephropathy: a literature review. Medwave. 2017;17(01):e6839-e6839. doi: 10.5867/medwave.2017.01.6839
Doshi SM, Friedman AN. Diagnosis and Management of Type 2 Diabetic Kidney Disease. Clin J Am Soc Nephrol. 2017;12(8):1366-1373. doi: 10.2215/CJN.11111016
Batchelor EK, Kapitsinou P, Pergola PE, Kovesdy CP, Jalal DI. Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment. J Am Soc Nephrol. 2020;31(3):456-468. doi: 10.1681/ASN.2019020213
Cases A, Egocheaga MI, Tranche S, et al. Anemia en la enfermedad renal crónica: protocolo de estudio, manejo y derivación a Nefrología. Aten Primaria. 2018;50(1):60-64. doi: 10.1016/j.aprim.2017.09.007
Li L, Zheng X, Deng J, Zhou J, Ou J, Hong T. Ferric citrate for the treatment of hyperphosphatemia and anemia in patients with chronic kidney disease: a meta-analysis of randomized clinical trials. Ren Fail. 2022;44(1):1113-1123. doi: 10.1080/0886022X.2022.2094273
Gasche C, Ahmad T, Tulassay Z, et al. Ferric Maltol Is Effective in Correcting Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis. 2015;21(3):579-588. doi: 10.1097/MIB.0000000000000314
Umanath K, Jalal DI, Greco BA, et al. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD. J Am Soc Nephrol. 2015;26(10):2578-2587. doi: 10.1681/ASN.2014080842
Elli L, Ferretti F, Branchi F, et al. Sucrosomial Iron Supplementation in Anemic Patients with Celiac Disease Not Tolerating Oral Ferrous Sulfate: A Prospective Study. Nutrients. 2018;10(3):330. doi: 10.3390/nu10030330
Ribeiro M, Fonseca L, Anjos JS, et al. Oral iron supplementation in patients with chronic kidney disease: Can it be harmful to the gut microbiota? Nutr Clin Pract. 2022;37(1):81-93. doi: 10.1002/ncp.10662
Singh AK, Cizman B, Carroll K, et al. Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients. JAMA Intern Med. 2022;182(6):592. doi: 10.1001/jamainternmed.2022.0605
Dhillon S. Desidustat: First Approval. Drugs. 2022;82(11):1207-1212. doi: 10.1007/s40265-022-01744-w
Fujikawa R, Nagao Y, Fujioka M, Akizawa T. Treatment of anemia associated with chronic kidney disease with the HIF prolyl hydroxylase inhibitor enarodustat: A review of the evidence. Therapeutic Apheresis and Dialysis. 2022;26(4):679-693. doi: 10.1111/1744-9987.13820
Akizawa T, Macdougall IC, Berns JS, et al. Iron Regulation by Molidustat, a Daily Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, in Patients with Chronic Kidney Disease. Nephron. 2019;143(4):243-254. doi: 10.1159/000502012
Li ZL, Tu Y, Liu BC. Treatment of Renal Anemia with Roxadustat: Advantages and Achievement. Kidney Diseases. 2020;6(2):65-73. doi: 10.1159/000504850
Eckardt KU, Agarwal R, Farag YM, et al. Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials. Nephrol Dial Transplant. 2021;36(11):2039-2048. doi: 10.1093/ndt/gfaa204
Renders L, Budde K, Rosenberger C, et al. First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis. PLoS One. 2019;14(3):e0212023. doi: 10.1371/journal.pone.0212023
Cardoso MP, Pereira LAL. Native vitamin D in pre-dialysis chronic kidney disease. Nefrología. 2019;39(1):18-28. doi: 10.1016/j.nefro.2018.07.004
Akarsu S, Taskin E, Yilmaz E, Yilmaz H, Kilic M, Aygun AD. Treatment of Iron Deficiency Anemia with Intravenous Iron Preparations. Acta Haematol. 2006;116(1):51-57. doi: 10.1159/000092348
Shepshelovich D, Rozen-Zvi B, Avni T, Gafter U, Gafter-Gvili A. Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: An Updated Systematic Review and Meta-analysis. Am J Kidney Dis. 2016;68(5):677-690. doi: 10.1053/j.ajkd.2016.04.018
Ohira Y, Chen CS, Hegenauer J, Saltman P. Adaptations of Lactate Metabolism in Iron-Deficient Rats. Exp Biol Med. 1983;173(2):213-216. doi: 10.3181/00379727-173-41633
Gutiérrez L, Morales MP, Lázaro FJ. Magnetic and structural study of the state of iron in the oral haematinic ferrimannitol ovoalbumin. J Inorg Biochem. 2006;100(3):413-417. doi: 10.1016/j.jinorgbio.2006.01.006
Bailie GR, Larkina M, Goodkin DA, et al. Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality. Kidney Int. 2015;87(1):162-168. doi: 10.1038/ki.2014.275
Fishbane S, Block GA, Loram L, et al. Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia. J Am Soc Nephrol. 2017;28(6):1851-1858. doi: 10.1681/ASN.2016101053
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 European Journal of Clinical and Experimental Medicine
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.
